Liposomal Cytarabine-Daunorubicin CPX-351 in Treating Patients With Untreated Myelodysplastic Syndrome or Acute Myeloid Leukemia

• Sponsor: Fred Hutchinson Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT01804101
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 48
• Locations: 2
• Arms: 2
• Actual Duration (Months): 44.2
• Patients Per Site: 24
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

This randomized clinical trial studies liposomal cytarabine-daunorubicin CPX-351 in treating patients with untreated myelodysplastic syndrome or acute myeloid leukemia. Drugs used in chemotherapy, such as liposomal cytarabine-daunorubicin CPX-351, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

Condition or Disease	Intervention/Treatment	Phase
Acute Biphenotypic Leukemia; Acute Myeloid Leukemia; Myelodysplastic Syndrome; Untreated Adult Acute Myeloid Leukemia	Other: Laboratory Biomarker Analysis; Drug: Liposomal Cytarabine-Daunorubicin CPX-351	N/A

Detailed Description

PRIMARY OBJECTIVES:

1. Estimate whether the 32 units/m^{2 or the 64 units/m}2 or both dose levels of CPX-351 (liposomal cytarabine-daunorubicin CPX-351) are likely to improve treatment-related mortality (TRM) rate while keeping the complete remission (CR) rate constant in patients with untreated high-risk myelodysplastic syndrome (MDS) or non-acute promyelocytic leukemia (APL) acute myeloid leukemia (AML) at high risk of TRM.

SECONDARY OBJECTIVES:

1. Describe the CR/CR with incomplete platelet count recovery (CRp) rate after up to 4 cycles of induction/re-induction therapy.

2. Describe the event-free survival, disease-free survival, and overall survival of patients who achieve CR/CRp.

3. Estimate the frequency and severity of regimen-associated toxicities.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I:

INDUCTION/RE-INDUCTION: Patients receive lower-dose liposomal cytarabine-daunorubicin CPX-351 intravenously (IV) over 90 minutes on days 1, 3, and 5. Treatment repeats every 40 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients achieving CR or CRp continue on to consolidation.

CONSOLIDATION: Patients receive lower-dose liposomal cytarabine-daunorubicin CPX-351 IV over 90 minutes on days 1 and 3. Treatment repeats every 40 days for 4 courses in the absence of disease progression or unacceptable toxicity.

ARM II: (closed to accrual effective 4/21/14) INDUCTION/RE-INDUCTION: Patients receive higher-dose liposomal cytarabine-daunorubicin CPX-351 IV over 90 minutes on days 1, 3, and 5. Treatment repeats every 40 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients achieving CR or CRp continue on to consolidation.

CONSOLIDATION: Patients receive higher-dose liposomal cytarabine-daunorubicin CPX-351 IV over 90 minutes on days 1 and 3. Treatment repeats every 40 days for 4 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 1 month.

Study Design

• Study Type: Interventional
• Actual Enrollment: 48 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Liposomal Cytarabine and Daunorubicin (CPX-351) for Adults With Untreated High-Risk MDS and Non-APL AML at High Risk of Treatment-Related Mortality
• Actual Study Start Date: May 7, 2013
• Actual Primary Completion Date: Jan 10, 2017
• Actual Study Completion Date: Jan 10, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I (lower-dose liposomal cytarabine-daunorubicin CPX-351) INDUCTION/RE-INDUCTION: Patients receive lower-dose liposomal cytarabine-daunorubicin CPX-351 IV over 90 minutes on days 1, 3, and 5. Treatment repeats every 40 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients achieving CR or CRp continue on to consolidation. CONSOLIDATION: Patients receive lower-dose liposomal cytarabine-daunorubicin CPX-351 IV over 90 minutes on days 1 and 3. Treatment repeats every 40 days for 4 courses in the absence of disease progression or unacceptable toxicity.	Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Liposomal Cytarabine-Daunorubicin CPX-351; Given IV; Other Names: CPX-351 Cytarabine-Daunorubicin Liposome for Injection Liposomal AraC-Daunorubicin CPX-351
Experimental: Arm II (closed to accrual effective 4/21/14) INDUCTION/RE-INDUCTION: Patients receive higher-dose liposomal cytarabine-daunorubicin CPX-351 IV over 90 minutes on days 1, 3, and 5. Treatment repeats every 40 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients achieving CR or CRp continue on to consolidation. CONSOLIDATION: Patients receive higher-dose liposomal cytarabine-daunorubicin CPX-351 IV over 90 minutes on days 1 and 3. Treatment repeats every 40 days for 4 courses in the absence of disease progression or unacceptable toxicity.	Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Liposomal Cytarabine-Daunorubicin CPX-351; Given IV; Other Names: CPX-351 Cytarabine-Daunorubicin Liposome for Injection Liposomal AraC-Daunorubicin CPX-351

Outcome Measures

Primary Outcome Measures

1. Treatment-related Mortality Rate. (TRM) [Up to 1 month after completion of study treatment]

   Estimate whether the 32 units/m2 or the 64 units/m2 or both dose levels of CPX-351 are likely to improve treatment-related mortality (TRM) rate while keeping the CR rate constant in patients with untreated high-risk MDS or non-APL AML at high risk of TRM.

Secondary Outcome Measures

1. Overall Remission Rate (CR+CRp) [Up to day 28]

   Overall Remission Rate for the CR/CR with incomplete platelet count recovery (CRp) rate after up to 4 cycles of induction/re-induction therapy.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Diagnosis of untreated "high-risk" MDS (>= 10% blasts) or AML other than acute promyelocytic leukemia (APL) with t(15;17)(q22;q12) or variants according to the 2008 World Health Organization (WHO) classification; patients with biphenotypic AML are eligible; outside diagnostic material is acceptable as long as peripheral blood and/or bone marrow slides are reviewed at the study institution and cytogenetic/molecular information is available

• Prior hydroxyurea for AML is permitted but should be discontinued prior to start of CPX-351 treatment

• Azacitidine, decitabine, lenalidomide, and growth factors are permitted for low-risk MDS (< 10% blasts); all treatments for MDS should be discontinued prior to start of CPX-351 treatment

• Treatment-related mortality (TRM) score >= 13.1 as calculated with simplified model

• Bilirubin < 2.0 mg/mL x upper limit of normal; this requirement reflects the excretion of CPX-351 by the liver

• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) < 4.0 x upper limit of normal; this requirement reflects the excretion of CPX-351 by the liver

• Left ventricular ejection fraction (LVEF) >= 40%, assessed within 28 days prior to registration, e.g. by multi gated acquisition (MUGA) scan or echocardiography, or other appropriate diagnostic modality

• Patients with symptoms/signs of hyperleukocytosis or white blood cell (WBC) > 100,000/uL can be treated with leukapheresis prior to enrollment

• Provide signed written informed consent

Exclusion Criteria:

• Refractory/relapsing blast crisis of chronic myelogenous leukemia (CML)

• Concomitant illness associated with a likely survival of < 1 year

• Active systemic fungal, bacterial, viral, or other infection, unless under treatment with anti-microbials and controlled/stable, as defined as being afebrile and hemodynamically stable for 24-48 hours

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Stanford Cancer Institute	Palo Alto	California	United States	94304
2	Fred Hutch/University of Washington Cancer Consortium	Seattle	Washington	United States	98109

Sponsors and Collaborators

• Fred Hutchinson Cancer Center
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Roland Walter, Fred Hutch/University of Washington Cancer Consortium

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Roland Walter, Principal Investigator, Fred Hutchinson Cancer Center
• ClinicalTrials.gov Identifier: NCT01804101
• Other Study ID Numbers: 2642.00; NCI-2013-00481; 2642; 2642.00; P30CA015704
• First Posted: Mar 5, 2013
• Last Update Posted: May 25, 2018
• Last Verified: Apr 1, 2018

• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Leukemia, Biphenotypic, Acute; Myelodysplastic Syndromes; Syndrome; Cytarabine; Daunorubicin

Study Results

Participant Flow

Arm/Group Title	Arm I (Lower-dose CPX-351)	Arm II (Higher Dose COX-351)
Arm/Group Description	INDUCTION/RE-INDUCTION: Patients receive lower-dose liposomal cytarabine-daunorubicin CPX-351 IV over 90 minutes on days 1, 3, and 5. Treatment repeats every 40 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients achieving CR or CRp continue on to consolidation. CONSOLIDATION: Patients receive lower-dose liposomal cytarabine-daunorubicin CPX-351 IV over 90 minutes on days 1 and 3. Treatment repeats every 40 days for 4 courses in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Liposomal Cytarabine-Daunorubicin CPX-351: Given IV	INDUCTION/RE-INDUCTION: Patients receive higher-dose liposomal cytarabine-daunorubicin CPX-351 IV over 90 minutes on days 1, 3, and 5. Treatment repeats every 40 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients achieving CR or CRp continue on to consolidation. CONSOLIDATION: Patients receive higher-dose liposomal cytarabine-daunorubicin CPX-351 IV over 90 minutes on days 1 and 3. Treatment repeats every 40 days for 4 courses in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Liposomal Cytarabine-Daunorubicin CPX-351: Given IV
Period Title: Overall Study
STARTED	38	10
COMPLETED	38	10
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Arm I (Lower-dose Liposomal Cytarabine-daunorubicin CPX-351)	Arm II (Closed to Accrual Effective 4/21/14)	Total
Arm/Group Description	INDUCTION/RE-INDUCTION: Patients receive lower-dose liposomal cytarabine-daunorubicin CPX-351 IV over 90 minutes on days 1, 3, and 5. Treatment repeats every 40 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients achieving CR or CRp continue on to consolidation. CONSOLIDATION: Patients receive lower-dose liposomal cytarabine-daunorubicin CPX-351 IV over 90 minutes on days 1 and 3. Treatment repeats every 40 days for 4 courses in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Liposomal Cytarabine-Daunorubicin CPX-351: Given IV	INDUCTION/RE-INDUCTION: Patients receive higher-dose liposomal cytarabine-daunorubicin CPX-351 IV over 90 minutes on days 1, 3, and 5. Treatment repeats every 40 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients achieving CR or CRp continue on to consolidation. CONSOLIDATION: Patients receive higher-dose liposomal cytarabine-daunorubicin CPX-351 IV over 90 minutes on days 1 and 3. Treatment repeats every 40 days for 4 courses in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Liposomal Cytarabine-Daunorubicin CPX-351: Given IV	Total of all reporting groups
Overall Participants	38	10	48
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	10 26.3%	2 20%	12 25%
>=65 years	28 73.7%	8 80%	36 75%
Sex: Female, Male (Count of Participants)
Female	13 34.2%	3 30%	16 33.3%
Male	25 65.8%	7 70%	32 66.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	38 100%	10 100%	48 100%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	3 7.9%	0 0%	3 6.3%
Black or African American	0 0%	0 0%	0 0%
White	35 92.1%	10 100%	45 93.8%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
United States	38 100%	10 100%	48 100%

Outcome Measures

1. Primary Outcome

Title	Treatment-related Mortality Rate. (TRM)
Description	Estimate whether the 32 units/m2 or the 64 units/m2 or both dose levels of CPX-351 are likely to improve treatment-related mortality (TRM) rate while keeping the CR rate constant in patients with untreated high-risk MDS or non-APL AML at high risk of TRM.
Time Frame	Up to 1 month after completion of study treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I (Lower-dose Liposomal Cytarabine-daunorubicin CPX-351)	Arm II (Closed to Accrual Effective 4/21/14)
Arm/Group Description	INDUCTION/RE-INDUCTION: Patients receive lower-dose liposomal cytarabine-daunorubicin CPX-351 IV over 90 minutes on days 1, 3, and 5. Treatment repeats every 40 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients achieving CR or CRp continue on to consolidation. CONSOLIDATION: Patients receive lower-dose liposomal cytarabine-daunorubicin CPX-351 IV over 90 minutes on days 1 and 3. Treatment repeats every 40 days for 4 courses in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Liposomal Cytarabine-Daunorubicin CPX-351: Given IV	INDUCTION/RE-INDUCTION: Patients receive higher-dose liposomal cytarabine-daunorubicin CPX-351 IV over 90 minutes on days 1, 3, and 5. Treatment repeats every 40 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients achieving CR or CRp continue on to consolidation. CONSOLIDATION: Patients receive higher-dose liposomal cytarabine-daunorubicin CPX-351 IV over 90 minutes on days 1 and 3. Treatment repeats every 40 days for 4 courses in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Liposomal Cytarabine-Daunorubicin CPX-351: Given IV
Measure Participants	38	10
Count of Participants [Participants]	6 15.8%	2 20%

2. Secondary Outcome

Title	Overall Remission Rate (CR+CRp)
Description	Overall Remission Rate for the CR/CR with incomplete platelet count recovery (CRp) rate after up to 4 cycles of induction/re-induction therapy.
Time Frame	Up to day 28

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I (Lower-dose CPX-351)	Arm II (Higher Dose COX-351)
Arm/Group Description	INDUCTION/RE-INDUCTION: Patients receive lower-dose liposomal cytarabine-daunorubicin CPX-351 IV over 90 minutes on days 1, 3, and 5. Treatment repeats every 40 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients achieving CR or CRp continue on to consolidation. CONSOLIDATION: Patients receive lower-dose liposomal cytarabine-daunorubicin CPX-351 IV over 90 minutes on days 1 and 3. Treatment repeats every 40 days for 4 courses in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Liposomal Cytarabine-Daunorubicin CPX-351: Given IV	INDUCTION/RE-INDUCTION: Patients receive higher-dose liposomal cytarabine-daunorubicin CPX-351 IV over 90 minutes on days 1, 3, and 5. Treatment repeats every 40 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients achieving CR or CRp continue on to consolidation. CONSOLIDATION: Patients receive higher-dose liposomal cytarabine-daunorubicin CPX-351 IV over 90 minutes on days 1 and 3. Treatment repeats every 40 days for 4 courses in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Liposomal Cytarabine-Daunorubicin CPX-351: Given IV
Measure Participants	38	10
Count of Participants [Participants]	10 26.3%	1 10%

Adverse Events

Time Frame	3 years
Adverse Event Reporting Description	SAE reporting per our institution, is if it's related and unexpected. None of our AE's met this criteria per protocol. AE's are were review by study coordinator and PI threw medical records and outside records from patients other physicians.
Arm/Group Title	Arm I (Lower-dose Liposomal Cytarabine-daunorubicin CPX-351)		Arm II (Closed to Accrual Effective 4/21/14)
Arm/Group Description	INDUCTION/RE-INDUCTION: Patients receive lower-dose liposomal cytarabine-daunorubicin CPX-351 IV over 90 minutes on days 1, 3, and 5. Treatment repeats every 40 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients achieving CR or CRp continue on to consolidation. CONSOLIDATION: Patients receive lower-dose liposomal cytarabine-daunorubicin CPX-351 IV over 90 minutes on days 1 and 3. Treatment repeats every 40 days for 4 courses in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Liposomal Cytarabine-Daunorubicin CPX-351: Given IV		INDUCTION/RE-INDUCTION: Patients receive higher-dose liposomal cytarabine-daunorubicin CPX-351 IV over 90 minutes on days 1, 3, and 5. Treatment repeats every 40 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients achieving CR or CRp continue on to consolidation. CONSOLIDATION: Patients receive higher-dose liposomal cytarabine-daunorubicin CPX-351 IV over 90 minutes on days 1 and 3. Treatment repeats every 40 days for 4 courses in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Liposomal Cytarabine-Daunorubicin CPX-351: Given IV
All Cause Mortality
	Arm I (Lower-dose Liposomal Cytarabine-daunorubicin CPX-351)		Arm II (Closed to Accrual Effective 4/21/14)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/38 (26.3%)		5/10 (50%)
Serious Adverse Events
	Arm I (Lower-dose Liposomal Cytarabine-daunorubicin CPX-351)		Arm II (Closed to Accrual Effective 4/21/14)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/38 (0%)		0/10 (0%)
Other (Not Including Serious) Adverse Events
	Arm I (Lower-dose Liposomal Cytarabine-daunorubicin CPX-351)		Arm II (Closed to Accrual Effective 4/21/14)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	38/38 (100%)		10/10 (100%)
Blood and lymphatic system disorders
epistaxis	2/38 (5.3%)	2	0/10 (0%)	0
Thrombocytopenia	7/38 (18.4%)	7	2/10 (20%)	2
Leukopenia	3/38 (7.9%)	3	1/10 (10%)	1
Endocrine disorders
Increased Creatinine	3/38 (7.9%)	3	0/10 (0%)	0
Gastrointestinal disorders
Constipation	5/38 (13.2%)	5	0/10 (0%)	0
Diarrhea	3/38 (7.9%)	3	0/10 (0%)	0
General disorders
Fatigue	8/38 (21.1%)	8	2/10 (20%)	2
Edema	5/38 (13.2%)	5	0/10 (0%)	0
Infections and infestations
Neutroprenic Fever	5/38 (13.2%)	5	2/10 (20%)	2
PICC Line infection	1/38 (2.6%)	1	1/10 (10%)	1
Neutropenia	9/38 (23.7%)	9	3/10 (30%)	3
hypoxemia	2/38 (5.3%)	2	1/10 (10%)	1
Metabolism and nutrition disorders
Nausea	4/38 (10.5%)	4	1/10 (10%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.